Process for producing quinazolin-4-one and derivatives thereof

ABSTRACT

A process for preparing quinazolin-4-one or its derivative by reacting anthranilic acid or its derivative with formic acid or its derivative in the presence of ammonia, or by reacting ammonium anthranilate or its derivative with formic acid or its derivative.

FIELD OF THE INVENTION

The present invention relates to a process for preparingquinazolin-4-one or its derivatives from anthranilic acid or itsderivatives or ammonium anthranilate or its derivatives. Thequinazolin-4-one and its derivatives are useful as intermediates orstarting compounds for preparing pharmaceutically active compounds oragricultural chemicals.

BACKGROUND OF THE INVENTION

The following processes are known for preparing quinazolin-4-one or itsderivatives from anthranilic acid or its derivatives.

1) EP 1029853 discloses a process for preparing 6-iodoquinazolin-4-oneby reacting 5-iodoanthranilic acid with formamidine acetate in ethanolfor 20 hours. This process has problems in that the reaction period islong, and it is necessary to use expensive formamidine in an excessiveamount.

2) Chem. Pharm. Bull., 46, 1926 (1998) describes a process for preparingquinazolin-4-one by reacting anthranilic acid with formamide. Thisprocess has a problem in that teratogenetic formamide is used in anexcessive amount.

Thus, these processes have various problems, and hence are notsatisfactory as industrially employable processes for preparingquinazolin-4-one or its derivatives.

SUMMARY OF THE INVENTION

The present invention has an object to provide an industriallyadvantageous simple process for preparing quinazolin-4-one or itsderivatives from anthranilic acid or its derivatives or ammoniumanthranilate or its derivatives in high yields under moderateconditions.

The present invention resides in a process for preparingquinazolin-4-one or a derivative thereof having the formula (2):

in which each of R¹, R², R³ and R⁴ independently represents a hydrogenatom, a halogen atom, or a group that does not participate in thefollowing reaction and may have a substituent, or R¹, R², R³ and R⁴ maybe combined to form a ring, which is characterized in that ananthranilic acid or a derivative thereof having the formula (1):

in which each of R¹, R², R³ and R⁴ has the same meaning as above, isreacted with formic acid or a derivative thereof in the presence ofammonia.

The invention further relates to a process for preparingquinazolin-4-one or a derivative thereof having the above-mentionedformula (2) which is characterized in that ammonium anthranilate or aderivative thereof having the formula (3):

in which each of R¹, R², R³ and R⁴ independently represents a hydrogenatom, a halogen atom, or a group that does not participate in thefollowing reaction and may have a substituent, or R¹, R², R³ and R⁴ maybe combined to form a ring, is reacted with formic acid or a derivativethereof.

DETAILED DESCRIPTION OF THE INVENTION

The anthranilic acid or a derivative thereof employed in the inventionis represented by the above-mentioned formula (1). In the formula (1),each of R¹, R², R³ and R⁴ is the same or different and is a hydrogenatom, a halogen atom, or a group that does not participate in thereaction and may have a substituent. In more detail, each is hydrogen,alkyl, cycloalkyl, aralkyl, aryl, halogen, hydroxyl, alkoxy, alkylthio,nitro, cyano, carbonyl, or amino (not for R¹). Otherwise, R¹, R², R³ andR⁴ may be combined to form a ring. The alkyl contained in these groupspreferably has 1 to 12 carbon atoms.

Examples of the alkyl groups include methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl, nonyl, and decyl. These groups can be anyof isomers. Examples of the cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.Examples of the aralkyl groups include benzyl, phenethyl, andphenylpropyl. These groups can be any of isomers. Examples of the arylgroups include phenyl, p-tolyl, naphthyl, and anthranyl. These groupscan be any of isomers. Examples of halogen atoms include fluorine,chlorine, bromine, and iodine. Examples of the alkoxy groups includemethoxy, ethoxy, and propoxy. These groups can be any of isomers.Examples of the alkylthio groups include methylthio, ethylthio, andpropylthio. These groups can be any of isomers.

The above-mentioned alkyl, cycloalkyl, aralkyl, aryl, alkoxy, alkylthio,and amino(not for R¹) may have a substituent. Examples of thesubstituents include a substituent bonded via a carbon atom, asubstituent bonded via an oxygen atom, a substituent bonded via anitrogen atom, a substituent bonded via a sulfur atom, and a halogenatom.

Examples of the substituents bonded via a carbon atom include alkylgroups such as methyl, ethyl, propyl, butyl, pentyl, and hexyl;cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl; alkenyl groups such as vinyl, allyl, propenyl,cyclopropenyl, cyclobutenyl, and cyclopentenyl; heterocyclic alkenylgroups such as pyrrolidinyl, pyrrolyl, furyl, and thienyl; aryl groupssuch as phenyl, tolyl, xylyl, biphenylyl, naphthyl, anthryl, andphenanthoryl; acyl groups (may be acetallized) such as formyl, acetyl,propionyl, acryloyl, pivaloyl, cyclohexylcarbonyl, benzoyl, naphthoyl,and toluoyl; carboxyl groups; alkoxycarbonyl groups such asmethoxycarbonyl and ethoxycarbonyl; aryloxycarbonyl groups such asphenoxycarbonyl; halogenated alkyl groups such as trifluoromethyl; andcyano group. These groups can be any of isomers.

Examples of the substituents bonded via an oxygen atom include hydroxyl;alkoxy groups such as methoxy, ethoxy, propoxy, butoxy, pentyloxy,hexyloxy, heptyloxy, and benzyloxy; and aryloxy groups such as phenoxy,toluyloxy, and naphthyloxy. These groups can be any of isomers.

Examples of the substituents bonded via a nitrogen atom include primaryamino groups such as methylamino, ethylamino, butylamino,cyclohexylamino, phenylamino, and naphthylamino; secondary amino groupssuch as dimethylamino, diethylamino, dibutylamino, methylethylamino,methylbutylamino, and diphenylamino; heterocyclic amino groups such asmorpholino, piperidino, piperazinyl, pyrazolidinyl, pyrrolidino, andindolyl; and imino group. These groups can be any of isomers.

Examples of the substituents bonded via a sulfur atom include mercapto;thioalkoxy groups such as thiomethoxy, thioethoxy, and thiopropoxy; andthioaryloxy groups such as thiophenoxy, thiotoluyloxy, andthionaphthyloxy. These groups can be any of isomers.

Examples of the halogen atoms include fluorine, chlorine, bromine, andiodine.

The ammonium anthranilate and its derivatives employable in theinvention are represented by the aforementioned formula (3). R¹, R², R³and R⁴ seen in the formula (3) have the same meanings as describedhereinbefore.

Examples of the formic acid and its derivatives include formic acid;formic acid esters such as methyl formate and ethyl formate; andorthoformic acid esters such as methyl orthoformate and ethylorthoformate. Preferred are formic acid esters and orthoformic acidesters. More preferred are orthoformic acid esters. Specificallypreferred are methyl orthoformate and ethyl orthoformate.

The formic acid or its derivatives can be preferably employed in anamount of 1.0 to 10 moles, more preferably 1.1 to 3.0 moles, per onemole of anthranilic acid or its derivatives or ammonium anthranilate orits derivatives.

The ammonia employed in the reaction can be liquid ammonia or gaseousammonia. Preferred is a solution of ammonia in an organic solvent suchas alcohol (e.g., methanol) and ether (e.g., dioxane). In the lattercase, the ammonia solution is of a concentration of, preferably, 1 to 90wt. %, more preferably 3 to 30 wt. %. The ammonia is preferably employedin an amount of 1 to 60 moles, more preferably 2 to 20 moles, per onemole of anthranilic acid or its derivative.

The reaction of the invention can be conducted in the presence orabsence of a solvent. There are no limitation with respect to thesolvents employed in the reaction, provided that the solvents do notdisturb the reaction. Examples are alcohols such as methanol, ethanol,isopropyl alcohol, n-butyl alcohol, and t-butyl alcohol; amides such asN,N-dimethylformamide and N-methylpyrrolidone; ureas such asN,N′-dimethylimidazolidinone; sulfoxides such as dimethyl sulfoxide;aromatic hydrocarbons such as benzene, toluene, xylene, and mesitylene;halogenated aliphatic hydrocarbons such as methylene chloride,chloroform, and dichloroethane; nitrites such as acetonitrile andpropionitrile; and ethers such as diethyl ether, tetrahydrofuran, anddioxane. Preferred are alcohols. More preferred are methanol andethanol. These solvents can be employed singly or in combination.

The amount of the solvent employed in the reaction depends on thehomogeneity and stirring condition of the reaction mixture. It ispreferred that the solvent is employed in an amount of 0 to 50 g (morepreferably 0 to 20 g, most preferably 0 to 5 g) per one gram of theanthranilic acid or its derivative or ammonium anthranilate or itsderivative.

The reaction of the invention can be performed, for instance, by mixingand stirring the compounds to be involved in the invention. The reactionis preferably performed at a temperature of 40 to 200° C., morepreferably 50 to 150° C. There is no limitation with respect to thepressure for the reaction.

After the reaction is complete, the final product, i.e.,quinazolin-4-one or its derivative, can be isolated and purified by theconventional procedures such as concentration, distillation,recrystallization, and column chromatography.

The invention is further described by the following examples.

EXAMPLE 1

Preparation of quinazolin-4-one

In a 2-mL volume stainless steel pressure-resistant vessel were placed260 mg (1.9 mmol) of anthranilic acid, 403 mg (3.8 mmol) of methylorthoformate, and 1.2 mL (8.4 mmol) of 15 wt. % ammonia methanolsolution. The reaction was carried out at 120° C. for 2 hours. After thereaction was complete, the reaction mixture was cooled to roomtemperature and analyzed (according to absolute quantitative analysis)by high performance liquid chromatography. There was produced 278 mg(reaction yield: 100%) of quinazolin-4-one.

EXAMPLE 2

Preparation of 7-chloroquinazolin-4-one

In a 2-mL volume stainless steel pressure-resistant vessel were placed330 mg (1.9 mmol) of 4-chloroanthranilic acid, 403 mg (3.8 mmol) ofmethyl orthoformate, and 1.2 mL (8.4 mmol) of 15 wt. % ammonia methanolsolution. The reaction was carried out at 120° C. for 2 hours. After thereaction was complete, the reaction mixture was cooled to roomtemperature and analyzed (according to absolute quantitative analysis)by high performance liquid chromatography. There was produced 343 mg(reaction yield: 99%) of 7-chloroquinazolin-4-one.

EXAMPLE 3

Preparation of 6-iodoquinazolin-4-one

In a 2-mL volume stainless steel pressure-resistant vessel were placed500 mg (1.9 mmol) of 5-iodoanthranilic acid, 403 mg (3.8 mmol) of methylorthoformate, and 1.2 mL (8.4 mmol) of 15 wt. % ammonia methanolsolution. The reaction was carried out at 120° C. for 2 hours. After thereaction was complete, the reaction mixture was cooled to roomtemperature and analyzed (according to absolute quantitative analysis)by high performance liquid chromatography. There was produced 515 mg(reaction yield: 99%) of 6-iodoquinazolin-4-one.

EXAMPLE 4

Preparation of 6-iodoquinazolin-4-one

The procedures of Example 3 were repeated except that the reactiontemperature and reaction period were changed to 95° C. and 4 hours,respectively. There was produced 485 mg (reaction yield: 93%) of6-iodoquinazolin-4-one.

EXAMPLE 5

Preparation of 6-iodoquinazolin-4-one

The procedures of Example 3 were repeated except that the amount ofmethyl orthoformate was changed to 320 mg (3.0 mmol). There was produced514 mg (reaction yield: 99%) of 6-iodoquinazolin-4-one.

EXAMPLE 6

Preparation of 6-iodoquinazolin-4-one

In a 200 mL volume stainless steel pressure-resistant vessel equippedwith a thermometer, an pressure gauge, and a stirrer were placed 25.0 g(95 mmol) of 5-iodoanthranilic acid, 17.1 g (162 mmol) of methylorthoformate, and 50 mL (349 mmol) of 15 wt. % ammonia methanolsolution. The reaction was carried out at a temperature of 100-110° C.and a pressure of 0.5 MPa (gauge pressure) for 8 hours. After thereaction was complete, the reaction mixture was cooled to a temperatureof 0-10° C. and placed under reduced pressure to distill ammonia off.The residual reaction mixture was then stirred at 0° C. for one hour.The precipitated solid was collected by filtration and dried, to obtain24.3 g (isolated yield: 94%) of 6-iodoquinazolin-4-one as a pale graycrystalline product.

EXAMPLE 7

Preparation of 6-iodoquinazolin-4-one

In a 2-mL volume stainless steel pressure-resistant vessel were placed500 mg (1.9 mmol) of 5-iodoanthranilic acid, 342 mg (5.7 mmol) of methylformate, and 1.2 mL (8.4 mmol) of 15 wt. % ammonia methanol solution.The reaction was carried out at 150° C. for 4 hours. After the reactionwas complete, the reaction mixture was cooled to room temperature andanalyzed (according to absolute quantitative analysis) by highperformance liquid chromatography. There was produced 401 mg (reactionyield: 77%) of 6-iodoquinazolin-4-one.

EXAMPLE 8

Preparation of 6-iodoquinazolin-4-one

The procedures of Example 7 were repeated except that methyl formate waschanged to 263 mg (5.7 mmol) of formic acid. There was produced 302 mg(reaction yield: 58%) of 6-iodoquinazolin-4-one.

Reference Example 1

Preparation of Ammonium Anthranilate

In a 50 mL volume glass vessel equipped with a stirrer and a thermometerwere placed 5.0 g (36.5 mmol) of anthranilic acid and 20 mL (156 mmol)of 15 wt. % ammonia methanol solution. The reaction was carried out for2 hours at room temperature. After the reaction was complete, thereaction mixture was concentrated under reduced pressure, to obtain 5.0g (isolated yield: 94%) of ammonium anthranilate as white solid.

The physical characteristics of the ammonium anthranilate were describedbelow.

m.p. (sublimation): 145 to 146° C.

¹H-NMR (DMSO-d₆, δ (ppm)): 6.37-6.43 (1 H, m), 6.56 (1 H, dd, J=1.2, 8.1Hz), 6.95 (6 H, brs), 6.98-7.04 (1 H, m), 7.69-7.72 (1 H, dd, J=1.8, 7.8Hz).

EXAMPLE 9

Preparation of quinazolin-4-one

In a 2-mL volume stainless steel pressure-resistant vessel were placed280 mg (1.8 mmol) of ammonium anthranilate (prepared in the same manneras in Reference Example 1), 400 mg (3.6 mmol) of methyl orthoformate,and 1.5 mL of methanol. The reaction was carried out at 120° C. for 2hours. After the reaction was complete, the reaction mixture was cooledto room temperature and analyzed (according to absolute quantitativeanalysis) by high performance liquid chromatography. There was produced214 mg (reaction yield: 81%) of quinazolin-4-one.

Reference Example 2

Preparation of ammonium 4-chloroanthranilate

In a 50 mL volume glass vessel equipped with a stirrer and a thermometerwere placed 5.0 g (29.1 mmol) of 4-chloroanthranilic acid and 20 mL (156mmol) of 15 wt. % ammonia methanol solution. The reaction was carriedout for 2 hours at room temperature. After the reaction was complete,the reaction mixture was concentrated under reduced pressure, to obtain5.0 g (isolated yield: 95%) of ammonium 4-chloroanthranilate as whitesolid.

The physical characteristics of the ammonium 4-chloroanthranilate (whichwas a new compound) were described below.

m.p. (sublimation): 232 to 233° C.

¹H-NMR (DMSO-d₆, δ (ppm)): 6.43 (1 H, dd, J=2.4, 8.4 Hz), 6.69 (1 H, d,J=2.4 Hz), 7.0 (3 H, brs), 7.69 (1 H, d, J=8.4 Hz), 11.0 (3 H, brs).

EXAMPLE 10

Preparation of 7-chloroquinazolin-4-one

In a 2-mL volume stainless steel pressure-resistant vessel were placed340 mg (1.8 mmol) of ammonium 4-chloroanthranilate (prepared in the samemanner as in Reference Example 2), 400 mg (3.6 mmol) of methylorthoformate, and 1.5 mL of methanol. The reaction was carried out at120° C. for 2 hours. After the reaction was complete, the reactionmixture was cooled to room temperature and analyzed (according toabsolute quantitative analysis) by high performance liquidchromatography. There was produced 176 mg (reaction yield: 54%) of7-chloroquinazolin-4-one.

Reference Example 3

Preparation of ammonium 5-chloroanthranilate

In a 50 mL volume glass vessel equipped with a stirrer and a thermometerwere placed 5.0 g (29.1 mmol) of 5-chloroanthranilic acid and 20 mL (156mmol) of 15 wt. % ammonia methanol solution. The reaction was carriedout for 2 hours at room temperature. After the reaction was complete,the reaction mixture was concentrated under reduced pressure, to obtain5.0 g (isolated yield: 95%) of ammonium 5-chloroanthranilate as paleyellow solid.

The physical characteristics of the ammonium 5-chloroanthranilate (whichwas a new compound) were described below.

m.p. (sublimation): 161 to 162° C.

¹H-NMR (DMSO-d₆, δ (ppm)): 6.57 (1 H, d, J=8.4 Hz), 6.99 (1 H, dd,J=2.7, 8.4 Hz), 7.0 (3 H, brs), 7.65 (1 H, d, J=2.7 Hz), 11.0 (3 H,brs).

EXAMPLE 11

Preparation of 6-chloroquinazolin-4-one

In a 2-mL volume stainless steel pressure-resistant vessel were placed340 mg (1.8 mmol) of ammonium 5-chloroanthranilate (prepared in the samemanner as in Reference Example 3), 400 mg (3.6 mmol) of methylorthoformate, and 1.5 mL of methanol. The reaction was carried out at120° C. for 2 hours. After the reaction was complete, the reactionmixture was cooled to room temperature and analyzed (according toabsolute quantitative analysis) by high performance liquidchromatography. There was produced 307 mg (reaction yield: 94%) of6-chloroquinazolin-4-one.

EXAMPLE 12

Preparation of 6-chloroquinazolin-4-one

In a 2-mL volume stainless steel pressure-resistant vessel were placed340 mg (1.8 mmol) of ammonium 5-chloroanthranilate (prepared in the samemanner as in Reference Example 3), 400 mg (3.6 mmol) of methylorthoformate, and 1.5 mL of acetonitrile. The reaction was carried outat 120° C. for 2 hours. After the reaction was complete, the reactionmixture was cooled to room temperature and analyzed (according toabsolute quantitative analysis) by high performance liquidchromatography. There was produced 303 mg (reaction yield: 93%) of6-chloroquinazolin-4-one.

Reference Example 4

Preparation of ammonium 5-iodoanthranilate

In a 200 mL volume glass vessel equipped with a stirrer and athermometer were placed 10.0 g (38 mmol) of 5-iodoanthranilic acid and100 mL (780 mmol) of 15 wt. % ammonia methanol solution. The reactionwas carried out for 3 hours at room temperature. After the reaction wascomplete, the reaction mixture was concentrated under reduced pressure,to obtain 9.0 g (isolated yield: 85%) of ammonium 5-iodoanthranilate aspale red solid.

The physical characteristics of the ammonium 5-iodoanthranilate (whichwas a new compound) were described below.

m.p. (decomposition): 160° C.

1H-NMR (DMSO-d₆, δ (ppm)): 6.45 (1 H, d, J=8.7 Hz), 6.5 (3 H, brs), 7.25(1 H, dd, J=2.4, 8.7 Hz), 7.96 (1 H, d, J=2.4 Hz), 11.0 (3 H, brs).

EXAMPLE 13

Preparation of 6-iodoquinazolin-4-one

In a 2-mL volume stainless steel pressure-resistant vessel were placed530 mg (1.9 mmol) of ammonium 5-iodoanthranilate (prepared in the samemanner as in Reference Example 4), 403 mg (3.8 mmol) of methylorthoformate, and 1.5 mL of methanol. The reaction was carried out at120° C. for 2 hours. After the reaction was complete, the reactionmixture was cooled to room temperature and analyzed (according toabsolute quantitative analysis) by high performance liquidchromatography. There was produced 402 mg (reaction yield: 77%) of6-iodoquinazolin-4-one.

EXAMPLE 14

Preparation of 6-iodoquinazolin-4-one

In a 2-mL volume glass vessel equipped with a reflux condenser wereplaced 530 mg (1.9 mmol) of ammonium 5-iodoanthranilate (prepared in thesame manner as in Reference Example 4), 403 mg (3.8 mmol) of methylorthoformate, and 1.5 mL of n-butyl alcohol. The reaction was carriedout at 120° C. for 2 hours. After the reaction was complete, thereaction mixture was cooled to room temperature and analyzed (accordingto absolute quantitative analysis) by high performance liquidchromatography. There was produced 350 mg (reaction yield: 67%) of6-iodoquinazolin-4-one.

Utiliziation in Industry

According to the invention, quinazolin-4-one or its derivative can beprepared from anthranilic acid or its derivatives or ammoniumanthranilate or its derivative in a high yield under moderate conditionsby simple procedures.

1. A process for preparing quinazolin-4-one or a derivative thereofhaving the formula (2):

in which each of R¹, R², R³ and R⁴ independently represents a hydrogenatom, a halogen atom, or a group selected from the group consisting ofalkyl, cycloalkyl, aralkyl, aryl, hydroxyl, alkoxy, alkylthio, nitro,and cyano, wherein a compound having the formula (1):

in which each of R¹, R², R³ and R⁴ has the same meaning as above, isreacted with a formic acid ester or an orthoformic acid ester at atemperature in the range of 50 to 150° C. in the presence of ammonia. 2.The process for preparing quinazolin-4-one or a derivative thereofaccording to claim 1, wherein each of R¹, R², R³ and R⁴ independently isa hydrogen atom or a halogen atom.
 3. A process for preparingquinazolin-4-one or a derivative thereof having the formula (2):

in which each of R¹, R², R³ and R⁴ independently represents a hydrogenatom, a halogen atom, or a group selected from the group consisting ofalkyl, cycloalkyl, aralkyl, aryl, hydroxyl, alkoxy, alkylthio, nitro,and cyano, a compound having the formula (3):

in which each of R¹, R², R³ and R⁴ has the same meaning as above, isreacted with a formic acid ester or an orthoformic acid ester at atemperature in the range of 50 to 150° C.
 4. The process for preparingquinazolin-4-one or a derivative thereof according to claim 3, whereineach of R¹, R², R³ and R⁴ independently is a hydrogen atom or a halogenatom.